Analogs of parathyroid hormone

ABSTRACT

The present invention is directed to peptide analogues of fragment of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP), a method of using said analogues alone or in combination with a bisphosphonate or calcitonin to treat osteoporosis and pharmaceutical compositions comprising said analogues alone or in combination with a bisphosphonate or calcitonin.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of co-pending U.S.application Ser. No. 09/341,217, filed Jul. 7, 1999, which is thenational phase continuation application of International Application No.PCT/US97/22498, filed Dec. 8, 1997, which is a continuation-in-part ofco-pending U.S. application Ser. No. 08/813,534, filed Mar. 7, 1997,which is a continuation-in-part of co-pending U.S. application Ser. No.08/779,768, filed Jan. 7, 1997, which is a continuation-in-part of U.S.application Ser. No. 08/626,186, filed Mar. 29, 1996, now issued as U.S.Pat. No. 5,723,577, which claims the benefit of priority of U.S.Provisional Application No. 50/003,305, filed Sep. 6, 1995 and U.S.Provisional Application No. 60/001,105, filed Jul. 13, 1995.

BACKGROUND OF THE INVENTION

Parathyroid hormone (“PTH”) is a polypeptide produced by the parathyroidglands. The mature circulating form of the hormone is comprised of 84amino acid residues. The biological action of PTH can be reproduced by apeptide fragment of its N-terminus (e.g. amino acid residues 1 through34). Parathyroid hormone-related protein (“PTHrP”) is a 139 to 173 aminoacid-protein with N-terminal homology to PTH. PTHrP shares many of thebiological effects of PTH including binding to a common PTH/PTHrPreceptor. Tregear, et al., Endocrinal., 93:1349 (1983). PTH peptidesfrom many different sources, e.g., human, bovine, rat, chicken, havebeen characterized. Nissenson, et al., Receptor, 3:193 (1993).

PTH has been shown to both improve bone mass and quality, Dempster, etal., Endocrine Rev., 14:690 (1993); and Riggs, Amer. J. Med., 91 (Suppl.5B):37S (1991). The anabolic effect of intermittently administered PTHhas been observed in osteoporotic men and women either with or withoutconcurrent antiresorptive therapy. Siovik, et al., J. Bone Miner. Res.,1:377 (1986); Reeve, et al., Br. Med. J., 301:314 (1990); and Hesch,R-D., et al., Calcif. Tissue Int'l, 44:176 (1989).

SUMMARY OF THE INVENTION

In one aspect, the invention features a peptide of the formula (I).

wherein

-   A₁ is Ser, Ala, or Dap;-   A₂ is Ser, Thr; or Aib:-   A₅ is Leu, Nle, Ile, Cha, β-Nat, Trp, Pal, Acc, Phe or p-X-Phe, in    which X is OH, a halogen, or CH₃;-   A₇ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe, in    which X is OH, a halogen, or CH₃;-   A₈ is Met, Nva, Leu, Val, Ile, Cha, Acc, or Nle:-   A₁₁ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in    which X is OH, a halogen, or CH₃;-   A₁₂ is Gly, Acc, or Aib;-   A₁₅ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in    which X is OH, a halogen, or CH₃;-   A₁₆ is Ser, Asn, Ala, or Aib;-   A₁₇ is Ser, Thr, or Aib;-   A₁₈ is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha, or Aib;-   A₁₉ is Glu or Aib;-   A₂₁ is Val, Acc, Cha, or Met;-   A₂₂ is Acc or Glu;-   A₂₃ is Trp, Acc, or Cha;-   A₂₄ is Leu, Acc, or Cha;-   A₂₇ is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;-   A₂₈ is Leu, Acc, or Cha;-   A₂₉ is Gln, Acc, or Aib;-   A₃₀ is Asp or Lys;-   A₃₁ is Val, Leu, Nle, Acc, Cha, or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Asn or deleted;-   A₃₄ is Phe, Tyr, Amp, Aib, or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkyl, C₇₋₂₀ alkenyl,    C₇₋₂₀ phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀ phenylalkyl, C₁₁₋₂₀    naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂ hydroxyalkenyl, C₇₋₂₀    hydroxy-phenylalkyl, or C₁₁₋₂₀ hydroxynaphthylalkyl; and

R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂hydrocarbon moiety and Z is H, OH, CO₂H, or CONH₂; provided that atleast one of A₅, A₇, A₈, A₁₁, A₁₂, A₁₅, A₁₈, A₂₁, A₂₂, A₂₃, A₂₇, A₂₆,A₂₉, and A₃₁ is Acc; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the immediately foregoing peptide is where A₃is Ser; A₅ is Ile or Acc; A₇ is Leu, Acc, or Cha; A₈ is Acc, Met. Nva,Leu, Val, Ile, or Nle; A₁₁ is Leu, Acc, or Cha; A₁₂ is Acc or Gly; A₁₅is Leu, Acc, or Cha; A₁₆ is Asn or Aib; A₁₇ is Ser or Aib; A₁₈ is Acc,Met, or Nle; A₂₁ is Val or Acc; A₂₇ is Lys, hArg, Acc, or Cha; A₃₁ isVal, Leu, Nle, Acc, or Cha; A₃₂ is His; A₃₃ is Asn; A₃₄ is Phe, Tyr,Amp, or Aib; or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the immediately foregoing peptide, designatedGroup B, is where A₅ is Ile or Ahc; A₇ is Leu, Ahc, or Cha; A₈ is Ahc,Met, or Nle; A₁₁ is Leu, Ahc, or Cha; A₁₂ is Ahc or Gly; A₁₅ is Leu,Ahc, or Cha; A₁₈ is Met or Ahc; A₂₁ is Val or Ahc; A₂₂ is Glu or Ahc;A₂₃ is Trp, Ahc, or Cha; A₂₄ is Leu, Ahc, or Cha; A₂₇ is Lys, hArg, Ahc,or Cha; A₂₈ is Leu, Ahc, or Cha; A₂₉ is Gln, Ahc, or Aib; A₃₁ is Val,Leu, Nle, Ahc, or Cha; R₁ is H; R₂ is H; and R₃ is NH₂; or apharmaceutically acceptable salt thereof.

A preferred group of peptides of Group B is where at least one of A₇ ,A₁₁, A₁₅, A₂₃, A₂₄, A₂₇, A₂₈, or A₃₁ is Cha.

Another preferred group of peptides of Group B is where at least one ofA₁₆, A₁₇, A₁₉, A₂₉, or a₃₄ is Aib.

Preferred peptides of formula (I) are [Ahc⁷ ¹¹]hPTH(1-34)NH₂; [Ahc⁷ ¹¹,Nle⁸ ¹⁸, Tyr³⁴]hPTH(1-34)NH₂; [Ahc¹¹]hPTH(1-34)NH₂; [Ahc⁷ ¹¹¹⁵]hPTH(1-34)NH₂; [(Ahc⁷]hPTH(1-34)NH₂; [Ahc²³]hPTH(1-34)NH₂;[Ahc²⁴]hPTH(1-34)NH₂; [Nle⁸ ¹⁸, Ahc²⁷]hPTH(1-34)NH₂;[Ahc²⁸]hPTH(1-34)NH₂; [Ahc³¹]hPTH(1-34)NH₂; [Ahc²⁴ ²⁸ ³¹]hPTH(1-34)NH₂;[Ahc²⁴ ²⁸ ³¹, Lys³⁰]hPTH(1-34)NH₂; [Ahc²⁸ ³¹]hPTH(1-34)NH₂;[Ahc¹⁵]hPTH(1-34)NH₂; [Ahc²⁴ ²⁷, Aib²⁹, Lys³⁰]hPTH(1-34)NH₂; [Ahc²⁴ ²⁷,Aib²⁹, Lys³⁰, Leu³¹]hPTH(1-34)NH₂; [Ahc⁵]hPTH(1-34)NH₂;[Ahc¹²]hPTH(1-34)NH₂; [Ahc²⁷]hPTH(1-34)NH₂; [Ahc²⁹]hPTH(1-34)NH₂; [Ahc²⁴²⁷]hPTH(1-34)NH₂; [Ahc²⁴ ²⁷, Aib²⁹]hPTH(1-34)NH₂; [Ahc²⁴,Aib²⁹]hPTH(1-34)NH₂; [Ahc²⁷, Aib²⁹]hPTH(1-34)NH₂; [Ahc¹⁸]hPTH(1-34)NH₂;[Ahc⁸]hPTH(1-34)NH₂; [Ahc¹⁸ ²⁷, Aib²⁹]hPTH(1-34)NH₂; or [Ahc¹⁸ ²⁴ ²⁷,Aib²⁹]hPTH(1-34)NH₂; [Ahc²², Leu²⁷, Aib²⁹]hPTH(1-34)NH₂; [Ahc²⁴, Leu²⁷,Aib²⁹]hPTH(1-34)NH₂; [Ahc²²]hPTH(1-34)NH₂; and [Ahc²²,Aib²⁹]hPTH(1-34)NH₂; or a pharmaceutically acceptable salt thereof.

The invention also features peptides of the following formulae: [Cha²²²³, Glu²⁵, Lys²⁶ ³⁰, Leu²⁸, Aib²⁹]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵,Lys²⁶ ³⁰, Aib²⁹]hPTHrP(1-34) NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶, Aib²⁹,Nle³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³⁰ ³¹, Lys²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³⁰ ³¹,Lys²⁶]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶,Nle³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²³ ²⁸ ³¹, His¹⁴,Cha¹⁵, Glu²² ²⁵, Lys²⁶ ³⁰, Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³,Lys²⁶, Leu²⁸ ³¹, Aib²⁹, Nle³⁰]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵, Lys²⁶³⁰, Leu²⁸ ³¹ Aig²⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹,Lys²⁵, Nle³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹ ¹⁵]hPTHrP(1-34)NH₂; [Cha⁷ ⁸¹⁵]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Aib²⁵ ²⁹, Lys²⁶ ³⁰, Leu²⁸³¹]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Aib²⁵ ²⁹, Lys²⁶,Leu²⁸]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Aib²⁵ ²⁹,Lys²⁶]hPTHrP(1-34)NH₂; [Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Lys²⁶,Leu²⁸ ³¹, Aib²⁹, Nle³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Lys²⁶ ³⁰,Aib²⁹, Leu³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶, Aib²⁹³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁶ ²⁹,Lys³⁰]hPThrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Lys²⁶ ³⁰, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂or [Leu²⁷ Aib²⁹]hPTH(1-34)NH₂; or apharmaceutically acceptable salt thereof.

The following are examples of the peptides of the invention covered bythe above formula: [Glu²² ²⁵, Leu²³ ²⁸, Lys²⁶ ³⁰, Aib²⁹,Ahc³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Ahc²³, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶,Ahc³⁰]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Ahc²⁴, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁶ ³⁰,Ahc²⁷]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Aib²⁵ ²⁹, Lys²⁶ ³⁰,Ahc²⁷]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ³¹, Lys²⁶ ³⁰, Ahc²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Cha²², Ahc²³, Glu²⁵, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴ ²⁷, Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc¹⁸ ²⁴ ²⁷, Glu²², Cha²³, Lys²⁵ ²⁶, Leu²⁸,Aib²⁹(]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Ahc²⁴, Lyc²⁵ ²⁶, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶, Ahc²⁷, Aib²⁹,Nle³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹, Met⁸, Asn¹⁰, His¹⁴, Glu²²²⁵, Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰, Ahc²⁷, Aib²⁹]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵,Met⁸, Asn¹⁰, Leu¹¹ ²³ ²⁸ ³¹, His¹⁴, Cha¹⁵, Glu²² ²⁵, Lys²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Cha²², Ahc²³, Glu²⁵, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Ahc²³, Aib²⁵ ²⁹, Lys²⁶ ³⁰, Leu²⁸³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰,Ahc²⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Ahc²⁴⁾, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴ ²⁷, Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰,Aib²⁹]hPThrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Aib²⁵ ²⁹, Lys²⁶ ³⁰,Ahc²⁷]hPTHrP(1-34)NH₂; [Ahc²² ²⁷, Leu²³ ²⁸ ³¹, Aib²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Lys²⁵ ²⁶ ³⁰,Aib²⁹]hPTHrP 1-34)NH₂; [Glu²², Leu²³ ²⁵, Ahc²⁴ ²⁷, Lys²⁵ ²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Ahc²⁴ ²⁷, Lys²⁵ ²⁵ ³⁰, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Cha²³, Ahc²⁴ ²⁷, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Ahc²⁴ ²⁷, Lys²⁵ ²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴ ²⁷, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Ahc²⁴ ²⁷, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Ahc²⁴ ²⁷, Lys²⁵ ²⁶, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Cha²³, Ahc²⁴ ²⁷, Lys²⁵ ²⁶, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Lys²⁵ ²⁶, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Lys²⁵ ²⁶, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Lys²⁵ ²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Lys²⁵ ²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHRP(1-34)NH₂, [Glu²², Cha²³, Ahc²⁴, Lys²⁵ ²⁵, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶, Aib²⁹,Ahc³⁰]hPTHrP(1-34)NH₂; [Aib²² ²⁹, Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁸³⁰]hPTHrP(1-34)NH₂; [Cha²², Ahc²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰, Leu²⁸³¹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Ahc²⁴, Glu²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Ahc²⁷]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ³¹, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Ahc²⁸]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Glu²⁵ ²⁹, Lys²⁶,Ahc³⁰]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸, Glu²⁵ ²⁹, Lys²⁶ ³⁰, Ahc³¹,]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Ahc²³, Aib²⁵, Lys²⁶ ³⁰, Leu²⁸ ³¹,]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁶ ³⁰,Glu²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Ahc²⁴, Aib²⁵, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ³¹, Aib²⁵,Lys²⁶ ³⁰,Ahc²⁸]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸, Aib²⁵, Lys²⁶ ³⁰,Ahc³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁵,Ahc³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶, Ahc²⁷,Aib³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Ahc²⁴, Lys²⁶, Aib³⁰]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶,Aib³⁰]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸, Glu²⁵ ²⁹, Lys²⁶ ³⁰³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸, Lys²⁶ ³¹,Ahc³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸, Lys²⁶ ³⁰ ³¹,Ahc²⁷]hPTHrP(1-34)NH₂; [Ahc²², Cha²³, Glu²⁵, Lys²⁸ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²², Cha²³, Lys²⁵ ²⁶ ³⁰, Leu²⁸ ³¹, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²², Cha²³, Lys²⁵ ²⁶, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸, Arg²⁵, Lys²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴, Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁸ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴, Leu²³ ²⁸ ³¹, Lys²⁵ ²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴, Leu²³ ²⁸ ³¹, Lys²⁵ ²⁵,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴, Leu²³ ²⁸, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²² ²⁴, Leu²³ ²⁸, Arg²⁵, Lys²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴, Lys²⁵ ²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Ahc²⁴, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴, Arg²⁵, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴, Arg²⁵, Lys²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Ahc²⁴, Arg²⁵, Lys²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Ahc²³, Aib²⁵ ²⁹, Lys²⁶ ³⁰, Leu²⁸³¹,]hPTHrP(1-34)NH₂; [Glu²², Ahc²³, Aib²⁵ ²⁹, Lys²⁶,Leu²⁸]hPTHrP(1-34)NH₂; [Glu²², Ahc²³ ³¹, Aib²⁵ ²⁹, Lys²⁶,Leu²⁸]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸, Aib²⁵ ²⁹, Lys²⁶ ³⁰,Ahc^(31]hPTHrP()1-34)NH₂; [Glu²², Leu²³ ²⁸, Aib²⁵ ²⁹, Lys²⁶,Ahc³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁵, Ahc²⁴ ³¹, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; or [Glu²², Leu²³ ²⁸, Ahc²⁴ ³¹, Lys²⁵ ²⁶,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²², Leu²³ ²⁸ ³¹, Ahc²⁴, Aib²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to peptide variants ofPTH(1-34) of the following generic formula:

wherein

-   A₂ is Ser, Ala, or Dap;-   A₃ is Ser, Thr, or Aib;-   A₅ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which    X is OH, a halogen or CH₃;-   A₇ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₈ is Met, Nva, Leu, Val, Ile, Cha, or Nle;-   A₁₁ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which    X is OH, a halogen or CH₃;-   A₁₂ is Gly or Aib;-   A₁₅is Leu, Nle, Ile, Cha, β-Nal, Trp Pal, Phe, or p-X-Phe in which X    is OH, a halogen, or CH₃;-   A₁₆ is Ser, Asn, Ala or Aib;-   A₁₇ is Ser, Thr, or Aib;-   A₁₈ is Met, Nva, Leu, Val, lle, Nle, Cha or Aib;-   A₁₉ is Glu or Aib;-   A₂₁ is Val, Cha, or Met;-   A₂₃ is Trp or Cha;-   A₂₄ is Leu or Cha;-   A₂₇ is Lys, Aib, Leu, hArg, Gln, or Cha;-   A₂₈ is Leu or Cha;-   A₃₀ is Asp or Lys;-   A₃₁ is Val, Nle, Cha, or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Asn or deleted;-   A₃₄ is Phe, Tyr, Amp, Aib or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,    C₇₋₂₀ phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ is alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀ phenylalkyl, C₁₁₋₂₀    naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂ hydroxyalkenyl, C₇₋₂₀    hydroxy-phenylalkyl, or C₁₁₋₂₀ hydroxynaphthylalkyl; and-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H, or CONH₂;

provided that (i) at least one of A₅, A₇, A₈, A₁₁, A₁₅, A₁₈, A₂₁, A₂₃,A₂₄, A₂₇, A₂₈, and A₃₁ is Cha, or at least one of A₃, A₁₂, A₁₅, A₁₇,A₁₈, A₁₉, and A₃₄ is Aib; or that (ii) at least A₁ is Dap, A₇ is β-Nal,Trp, Pal, Phe, or p-X-Phe, A₁₅ is β-Nal, Trp, Pal, Phe, or p-X-Phe, A₂₇is hArg, or A₃₁ is Nle; or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to peptide variants ofPTH(1-34) of the following formula (II):

wherein

-   A₁ is Ser, Ala, or Dap;-   A₃ is Ser, Thr or Aib;-   A₅ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which    X is OH, a halogen, or CH₃;-   A₇ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₈ is Mel, Nva, Leu, Val, Ile, Cha, or Nle;-   A₁₁ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in whic X    is OH, a halogen, or CH₃;-   A₁₂ is Gly or Aib;-   A₁₅ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₁₆ is Ser, Asn, Ala, or Aib;-   A₁₇ is Ser, Thr, or Aib;-   A₁₈ is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;-   A₁₉ is Glu or Aib;-   A₂₁ is Val, Cha, or Met;-   A₂₃ is Trp or Cha;-   A₂₄ is Leu or Cha;-   A₂₇ is Lys, Aib, Leu, hArg, Gln, or Cha;-   A₂₈ is Leu or Cha;-   A₃₀ is Asp or Lys;-   A₃₁ is Val, Nle, Cha, or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Asn or deleted;-   a₃₄ is Phe, Tyr, Amp, Aib, or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkenyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R_(2 is COE) ₁    in which E₁ is C₁₋₁₂ alkyl C₂₋₁₂ alkenyl, C₇₋₂₀ phenylalkyl, C₁₁₋₂₀    naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂ hydroxyalkenyl, C₇₋₂₀    hydroxy-phenylalkyl, or C₁₁₋₂₀ hydroxynaphthylalkyl; and-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H, or CONH₂;

provided that (i) at least one of A₅, A₇, A₈, A₁₁, A₁₅, A₁₈, A₂₁, A₂₃,A₂₄, A₂₇, A₂₈, and A₃₁ is Cha, or at least one of A₃, A₁₂, A₁₆, A₁₇,A₁₈, A₁₉, and a₃₄ is Aib; and the peptide is not [Aib¹²,Tyr³⁴]hPTH(1-34)NH₂, or a pharmaceutically acceptable salt thereof.

A preferred group of peptides of formula (II), designated Group (i) iswhere at least one of A₇, a₁₁, A₁₅, A₂₃, A₂₄, A₂₇, A₂₈, and A₃₁ is Cha;or a pharmaceutically acceptable salt thereof.

A preferred group of peptides of Group (i), designated Group (ii) iswhere A₃ is Ser; A₅ is Ile; A₇ is Leu or Cha; A₈ is Met, Nva, Leu, Val,Ile, or Nle; A₁₁ is Leu or Cha; A₁₂ is Gly; A₁₅ is Leu or Cha; A₁₆ isAsn or Aib; A₁₇ is Ser; A₁₈ is Met or Nle; A₂₁ is Val; A₂₇ is Lys, hArg,or Cha; A₃₂ is His; A₃₁ is Val, Nle, or Cha; A₃₃ is Asn; A₃₄ is Phe,Tyr, amp, or Aib; R₁ is H; R₂ is H; and R₃ is NH₂; or a pharmaceuticallyacceptable salt thereof.

A preferred group of peptides of Group (ii), designated Group (iii), iswhere at least one of A₇ and A₁₁ is Cha; or a pharmaceuticallyacceptable salt thereof.

Preferred peptides of Group (iii) are [Cha⁷ ¹¹]hPTH(1-34)NH₂, [Cha⁷ ¹¹,Nle⁸ ¹⁸, Tyr³⁴]hPTH(1-34)NH₂; [Cha¹¹]hPTH(1-34)NH₂; [Cha⁷ ¹¹¹⁵]hPTH(1-34)NH₂; and [Cha⁷]hPTH(1-34)NH₂; or a pharmaceuticallyacceptable salt thereof.

Another preferred group of peptides of Group (ii), designated Group(iv), is where at least one of A₁₅, A₂₃, A₂₄, A₂₇, A₂₈, and A₃₁ is Cha;or a pharmaceutically acceptable salt thereof.

Preferred peptides of Group (iv) are [Cha²³]hPTH(1-34)NH₂,[Cha²⁴]hPTH(1-34)NH₂, [Nle⁸ ¹⁸, Cha²⁷]hPTH(1-34)NH₂,[Cha²⁸]hPTH(1-34)NH₂, [Cha³¹]hPTH(1-34)NH₂, [Cha²⁴ ²⁸ ³¹]hPTH(1-34)NH₂;[Cha²⁴ ²⁸ ³¹, Lys³⁰]hPTH(1-34)NH₂; [Cha²⁸ ³¹ ]hPTH(1-34)NH₂; and[Cha¹⁵]hPTH(1-34)NH₂; or a pharmaceutically acceptable salt thereof.

Another preferred group of peptides of formula (II), designated Group(v), is where at least one of A₃, A₁₂, A₁₆, A₁₇, A₁₈, A₁₉, and A₃₄ isAib; or a pharmaceutically acceptable salt thereof.

A preferred group of peptides of Group (v), designated Group (vi), iswhere A₃ is Ser or Aib; A₅ is Ile; A₇ is Leu or Cha; A₈ is Met, Nva,Leu, Val, Ile, or Nle; A₁₁ is Leu or Cha; A₁₅ is Leu or Cha; A₁₅ is Asnor Aib; A₁₈ is Met, Aib, or Nle; A₂₁ is Val; A₂₇ is Lys, Aib, Leu, hArg,or Cha; A₃₁ is Val, Nle, or Cha; A₃₂ is His; A₃₃ is Asn; A₃₄ is Phe,Tyr, Amp, or Aib; R₁ is H; R₂ is H; and R₃ is NH₂or a pharmaceuticallyacceptable salt thereof.

A preferred group of peptides of Group (vi), designated Group (vii), iswhere at least one of A₃, A₁₂, A₁₆, A₁₇, A₁₉, and A₃₄ is Aib; or apharmaceutically acceptable salt thereof.

Preferred peptides of Group (vii) are [Aib¹⁶]hPTH(1-34)NH₂,[Aib¹⁹]hPTH(1-34)NH₂, [Aib³⁴]hPTH(1-34)NH₂; [Aib¹⁵ ¹⁹]hPTH(1-34)NH₂;[Aib³]hPTH(1-34)NH₂; [Aib¹⁷]hPTH(1-34)NH₂; and [Aib¹²]hPTH(1-34)NH₂; ora pharmaceutically acceptable salt thereof.

Another preferred group of peptides of formula (II), designated Group(viii), is where at least one of A₇, A₁₁, A₁₅, A₂₃, A₂₄, A₂₇, a₂₈, andA₃₁ is Cha and at least one of A₃, A₁₂, A₁₆, A₁₇, A₁₈, A₁₉, and a₃₄ isAib; or a pharmaceutically acceptable salt thereof.

A preferred group of peptides of Group (viii), designated Group (ix), iswhere A₃ is Ser or Aib; A₅ is Ile; A₇ is Leu or Cha; A₈ is Met, Nva,Leu, Val, Ile, or Nle; a₁₁ is Leu or Cha; A₁₅ is Leu or Cha; A₁₆ is Asnor Aib; A₁₈ is Met, Aib, or Nle; A₂₁ is Val; A₂₇ is Lys, Aib, Leu, hArg,or Cha; A₃₁ is Val, Nle, or Cha; A₃₂ is His; A₃₃ is Asn; A₃₄ is Phe,Tyr, Amp, or Aib; R₁ is H; R₂ is H; and r₃ is NH₂; or a pharmaceuticallyacceptable salt thereof.

A preferred group of peptides of Group (ix), designated Group (x), iswhere at least one of A₇ and A₁₁ is Cha and at least one of A₁₆, A₁₉,and A₃₄ is Aib; or a pharmaceutically acceptable salt thereof.

Preferred peptides of Group (x) are [Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib¹⁶ ¹⁹,Tyr³⁴]hPTH(1-34)NH₂, [Cha⁷ ¹¹, Nle⁸ ¹⁸ ³¹, Aib¹⁶ ¹⁹,Tyr³⁴]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Aib¹⁹]hPTH(1-34)NH₂, [Cha⁷ ¹¹,Aib¹⁶]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib³⁴]hPTH(1-34)NH₂; or [Cha⁷¹¹, Aib¹⁹, Lys³⁰]hPTH(1-34)NH₂; or a pharmaceutically acceptable saltthereof.

Another preferred group of peptides of Group (ix), designated Group(xi), is where at least one of A₂₄, A₂₈, and A₃₁ is Cha and at least oneof A₁₅ and A₁₇ is Aib; or a pharmaceutically acceptable salt thereof.

Preferred peptides of Group (xi) are [Cha²⁸, Nle⁸ ¹⁸, Aib¹⁶ ¹⁹,Tyr³⁴]hPTH(1-34)NH₂, and [Cha²⁸, Aib¹⁸ ¹⁹]PTH(1-34)NH₂; or apharmaceutically acceptable salt thereof.

In another aspect, the present invention is directed to a peptide of theformula (III):

wherein

-   A₃ is Ser, Thr, or Aib;-   A₅ is Leu, Nle, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is    OH, a halogen, or CH₃;-   A₇ is Leu, Nle, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is    H, OH, a halogen, or CH₃;-   A₈ is Met, Nva, Leu, Val, Ile, Cha, or Nle;-   A₁₁ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₁₂ is Gly or Aib;-   A₁₅ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₁₆ is Ser, Asn, Ala, or Aib;-   A₁₇ is Ser, Thr, or Aib;-   A₁₈ is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;-   A₁₉ is Glu or Aib;-   A₂₁ is Val, Cha, or Met;-   A₂₃ is Trp or Cha;-   A₂₄ is Leu or Cha;-   A₂₇ is Lys, Aib, Leu, hArg, Gln, or Cha;-   A₂₈ is Leu or Cha;-   A₃₀ is Asp or Lys;-   a₃₁ is Val, Nle, Cha, or deleted;-   A₃₂ is His or deleted;-   A₃₃ Asn or deleted;-   A₃₄ is Phe, Tyr, Amp, Aib, or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,    C₇₋₂₀ phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀ phenylalkyl, C₁₁₋₂₀    naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂ hydroxyalkenyl, C₇₋₂₀    hydroxy-phenylalkyl, or C₁₁₋₂₀ hydroxynaphthylalkyl;-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H, or CONH₂;

provided that at least A₁ is Dap, A₇ is β-Nal, Trp, Pal, Phe, orp-X-Phe; A₁₅ is β-Nal, Trp, Pal, Phe, or p-X-Phe, A₂₇ is hArg, or A₃₁ isNle; or a pharmaceutically acceptable salt thereof.

A preferred group of peptides of formula (III) is where A₁ is Ser, Gly,or Dap; A₃ is Ser or Aib; A₈ is Met, Nva, Leu, Val, Ile, or Nle; A₁₈ isAsn or Aib; A₁₈ is Met, Aib, or Nle; A₂₁ is Val; A₂₇ is Lys, Aib, Leu,hArg, or Cha; A₃₁ is Val, Nle, or Cha; A₃₂ is His; A₃₃ is Asn; A₃₄ isPhe; Tyr, Amp, or Aib; R₁ is H; R₂ is H; and R₃ is NH₂; or apharmaceutically acceptable salt thereof.

Preferred peptides of the immediately foregoing peptides are[Nle³¹]hPTh(1-34)NH₂; [hArg²⁷]hPTH(1 -34)NH₂, and [Dap¹ Nle⁸ ¹⁸,Tyr³⁴]hPTH(1-34)NH₂; or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is directed to a peptide of theformula (IV):

wherein

-   A₂ is Ala, Ser, or Dap;-   A₃ is Ser or Aib;-   A₅ is His, Ile, or Cha;-   A₇ is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is    OH, a halogen, or CH₃;-   A₈ is Leu, Met, or Cha;-   A₁₀ is Asp or Asn;-   A₁₁ is Lys, Leu, Cha, Phe, or β-Nal;-   A₁₂ is Gly or Aib;-   A₁₄ is Ser or His;-   A₁₅ is Ile, or Cha;-   A₁₆ is Gln or Aib;-   A₁₇ is Asp or Aib;-   A₁₈ is Leu, Aib, or Cha;-   A₁₉ is Arg or Aib;-   A₂₂ is Phe, Glu, Aib, or Cha;-   A₂₃ is Phe, Leu, Lys, or Cha;-   A₂₄ is Leu, Lys, or Cha;-   A₂₅ is His, Aib, or Glu;-   A₂₆ is His, Aib, or Lys;-   A₂₇ is Leu, Lys, or Cha;-   A₂₈ is Ile, Leu, Lys, or Cha;-   A₂₉ is Ala, Glu, or Aib;-   A₃₀ is Glu, Cha, Aib, or Lys;-   A₃₁ is Leu, Cha, Lys, or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Thr or deleted;-   A₃₄ is Ala or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkanyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂, hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; and-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H or CONH₂;

provided that at least one of A₅, A₇, A₈, A₁₁, A₁₅, A₁₈, A₂₂, A₂₃, A₂₄,A₂₇, A₂₈, A₃₀, or A₃₁ is Cha or at least one of A₃, A₁₂, A₁₆, A₁₇, A₁₈,A₁₉, A₂₂, A₂₅, A₂₆, A₂₉, A₃₀, or A₃₄ is Aib; or a pharmaceuticallyacceptable salt thereof.

A preferred group of peptides of formula (V) is where A₂₂ is Phe or Cha;A₂₃ is Phe or Cha; A₂₅ is His; A₂₆ is His; A₂₇ is Leu or Cha; A₂₉ isAla; A₃₀ is Glu or Lys; A₃₁ is Ile or Cha; A₃₂ is His; A₃₃ is Thr; andA₃₄ is Ala; or a pharmaceutically acceptable salt thereof. Two preferredgroups of peptides of the immediately foregoing group of peptides iswhere at least one of A₇ and A₁₁ is Cha; or where at least one of A₁₅ orA₁₉ is Aib; or a pharmaceutically acceptable salt thereof.

Another preferred group of peptides of formula (IV), is where A₂₂ isGlu, Aib, or Cha; A₂₃ is Leu, Lys, or Cha; A₂₅ is Aib or Glu; A₂₅ is Aibor Lys; A₂₈ is Leu, Lys, or Cha; A₂₉ is Glu or Aib; A₃₀ is Cha, Aib, orLys; A₃₁ is Leu, Cha, or Lys; A₃₂ is His; A₃₃ is Thr; and A₃₄ is Ala; ora pharmaceutically acceptable salt thereof. Two preferred groups ofpeptides of the immediately foregoing group of peptides is where atleast one of A₇ and A₁₁ is Cha; or where at least one of A₁₆ or A₁₉ isAib; or a pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to a peptide of theformula (V):

wherein

-   A₁ is Ala, Ser or Dap;-   A₃ is Ser or Aib;-   A₅ is His, Ile or Cha;-   A₇ is Leu, Cha, Nle, η-Nal, Trp, Pal, Phe, or p-X-Phe in which X is    OH, a halogen or CH₃;-   A₈ is Leu, Met or Cha;-   A₁₀ is Asp or Asn;-   A₁₁ is Lys, Leu, Cha, Phe or β-Nal;-   A₁₂ is Gly or Aib;-   A₁₄ is Ser or His;-   A₁₅ is Ile or Cha;-   A₁₆ is Gln or Aib;-   A₁₇ is Asp or Aib;-   A₁₈ is Leu, Aib or Cha;-   A₁₉ is Arg or Aib;-   A₂₂ is Phe, Glu, Aib, Acc or Cha;-   A₂₃ is Phe, Leu, Lys, Acc or Cha;-   A₂₄ is Leu, Lys, Acc or Cha;-   A₂₅ is His, Aib or Glu;-   A₂₅ is His, Aib or Lys;-   A₂₇ is Leu, Lys, Acc or Cha;-   A₂₈ is Ile, Leu, Lys, Acc or Cha;-   A₂₉ is Ala, Glu or Aib;-   A₃₀ is Glu, Cha, Aib, Acc or Lys;-   A₃₁ is Ile, Leu, Cha, Lys, Acc or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Thr or deleted;-   A₃₄ is Ala or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkanyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂, hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; and-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H or CONH₂;

provided that at least one of A₂₃, A₂₄, A₂₇, A₂₈, or A₃₁ is Lys; or apharmaceutically acceptable salt thereof.

A preferred group of peptides of formula (V) is where A₂₂ is Glu, Aib,Acc, or Cha; A₂₃ is Leu, Lys, Acc or Cha; A₂₅ is Aib or Glu; A₂₆ is Aibor Lys; A₂₈ is Leu, Lys, Acc, or Cha; A₂₉ is Glu or Aib; A₃₀ is Cha,Aib, Acc, or Lys; A₃₁ is Leu, Cha, Acc, or Lys; A₃₂ is His; A₃₂ is Thr;and A₃₄ Ala; or a pharmaceutically acceptable salt thereof. Twopreferred groups of peptides of the immediately foregoing group ofpeptides is where at least one of A₇ and A₁₁ is Cha; or where at leastone of A₁₆ or A₁₉ is Aib; or a pharmaceutically acceptable salt thereof.

The following are examples of peptides of this invention as encompassedby formula (II): [Cha⁷]hPTH(1-34)NH₂; [Cha¹¹]hPTH(1-34)NH₂;[Cha¹⁵]hPTH(1-34)NH₂; [Cha⁷ ¹¹]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Nle⁸ ¹⁸,Tyr³⁴]hPTH(1-34) NH₂; [Cha²³]hPTH(1-34)NH₂; [Cha²⁴]hPTH(1-34)NH₂; [Nle⁸¹⁸, Cha²⁷; ]hPTH(1-34)NH₂; [Cha²⁸]hPTH(1-34)NH₂; [Cha³¹]hPTH(1-34)NH₂;[Cha²⁷]hPTH(1-34)NH₂; [Cha²⁷ ²⁹]hPTH(1-34)NH₂; [Cha²⁸]bPTH(1-34)NH₂;[Cha²⁸]rPTH(1-34)NH₂; [Cha²⁴ ²⁸ ³¹]hPTH(1-34)NH₂; [Aib¹⁵]hPTH(1-34)NH₂;[Aib¹⁹]hPTH(1-34)NH₂; [Aib³⁴]hPTH(1-34)NH₂; [Aib¹⁶ ¹⁹]hPTH(1-34)NH₂;[Aib¹⁶ ¹⁹ ³⁴]bPTH(1-34)NH₂; [Aib¹⁶ ³⁴]hPTH(1-34)NH₂; [Aib¹⁹³⁴]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib¹⁶ ¹⁹, Tyr³⁴]hPTH(1-34)NH₂;[Cha⁷ ¹¹, Nle⁸ ¹⁸ ³¹, Aib¹⁶ ¹⁹, Tyr³⁴]hPTH(1-34)NH₂; [Cha⁷,Aib¹⁶]hPTH(1-34)NH₂; [Cha¹¹, Aib¹⁶]hPTH(1-34)₂; [Cha⁷,Aib³⁴]hPTH(1-34)NH₂; [Cha¹¹, Aib³⁴]hPTH(1-34)NH₂; [Cha²⁷,Aib¹⁵]hPTH(1-34)NH₂; [Cha²⁷, Aib³⁴]hPTH(1-34)NH₂; [Cha²⁸,Aib¹⁶]hPTH(1-34)NH₂; [Cha²⁸, Aib³⁴]hPTH(1-34)NH₂; [Nle³¹]hPTH(1-34)NH₂;[hArg²⁷]hPTH(1-34)NH₂; [Dap¹, Nle⁸ ¹⁸, Tyr³⁴]hPTH(1-34)NH₂;[NLE³¹]bPTH(1-34)NH₂; [Nle³¹]rPTH(1-34)NH₂; [hArg²⁷]bPTH(1-34)NH₂;[hArg²⁷]rPTH(1-34)NH₂; [Cha⁷ ¹¹, Aib¹⁹, Lys³⁰]hPTH(1-34)NH₂;[Aib¹²]hPTH(1-34)NH₂; [Cha²⁴ ²⁸ ³¹, Lys³⁰]hPTH(1-34)NH₂; [Cha²⁸³¹]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib³⁴]hPTH(1-34)NH₂;[Aib³]hPTH(1-34)NH₂; [Cha⁸]hPTH(1-34)NH₂; [Cha¹⁵]hPTH(1-34)NH₂; [Cha⁷¹¹, Aib¹⁹]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Aib¹⁶ ]hPTH(1-34)NH₂;[Aib¹⁷]hPTH(1-34)NH₂; [Cha⁶]hPTH(1-34)NH₂;[Cha⁷ ¹¹ ¹⁵]hPTH(1-34)NH₂;[Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib¹⁹, Tyr³⁴]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Nle⁸ ¹⁸, Aib¹⁹,Lys³⁰, Tyr³⁴]hPTH(1-34)NH₂; [Cha⁷ ¹¹ ¹⁵]hPTH(1-34)NH₂;[Aib¹⁷]hPTH(1-34)NH₂; [Cha⁷ ¹¹, Leu²⁷]hPTH(1-34) NH₂; [Cha⁷ ¹¹ ¹⁵,Leu²⁷]hPTH(1-34)NH₂; [Cha⁷ ¹¹ ²⁷]hPTH(1-34)NH₂; [Cha⁷ ¹¹ ¹⁵ ²⁷]hPTH(1-34)NH₂; [Trp¹⁵]hPTH(1-34)NH₂; [Nal¹⁵]hPTH(1-34) NH₂; [Trp¹⁵,Cha²³]hPTH(1-34)NH₂; [Cha¹⁵ ²³]hPTH(1-34)NH₂; [Phe⁷ ¹¹]hPTH(1-34)NH₂;[Nal⁷ ¹¹]hPTH(1-34)NH₂; [Trp⁷ ¹¹]hPTH (1-34)NH₂; [Phe⁷ ¹¹ ¹⁵]hPTH(1-34)NH₂; [Nal⁷ ¹¹ ¹⁵]hPTH(1-34)NH₂; [Trp⁷ ¹¹ ¹⁵]hPTH(1-34)NH₂; and [Tyr⁷ ¹¹¹⁵]hPTH(1-34)NH₂.

The following are specific examples of peptides encompassed by one ormore of formulas (III) to (V), hereinabove: [Cha⁷]hPTHrP(1-34)NH₂;[Cha¹¹]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹]hPTHrP(1-34)NH₂; [Aib¹⁶,Tyr³⁴hPTHrP(1-34)NH₂; [Aib¹⁹]hPTHrP(1-34)NH₂; [Aib¹⁶ ¹⁹]hPTHrP(1-34)NH₂;[Cha⁷ ¹¹, Aib¹⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁸ ²⁷³⁰]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵ ²⁹, Leu²⁸ ³¹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰, Leu²⁶ ³¹]hPTHrP(1-34)NH₂;[Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶, Cha³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁸,Leu²³ ²⁸ ³¹, Lys^(25 Aib) ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ³¹,Lys²⁶ ²⁸ ³⁰]hPTHrP(1-34) NH₂; [Cha²² ²³ ²⁴ ²⁷ ²⁸ ³¹, Glu²⁶ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Cha²³ ²⁴ ²⁸ ³¹, Lys²⁶ ²⁷³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Cha²³ ²⁴ ²⁷ ³¹, Lys²⁶ ²⁸³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰, Cha²⁴ ²⁷ ²⁸³¹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶ ²⁷ ³⁰]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ³¹, Glu²⁵ ²⁹, Lys²⁶ ²⁸³⁰]hPTHrP(1-34)NH₂; [Cha²², Lys²³ ²⁶ ³⁰, Glu²⁵ ²⁹, Leu²⁵³¹]hPHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁶, Lys²⁶ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶,Aib³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁵ ²⁷ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Lys²³ ²⁶ ³⁰, Leu²⁸ ³¹, Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ³¹, Lys²⁶ ²⁸ ³⁰,Aib²⁹]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹ ²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ²⁷³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹ ²² ²³, Glu²⁵ ²⁹, Leu²⁸ ³¹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰, Leu²⁸³¹]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵ ²⁹, Leu²³ ³¹, Lys²⁶ ²⁸ ³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ¹¹, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶,Aib³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶³⁰]hPTHrP(1-34) NH₂; [Cha¹⁵ ²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ²⁷³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵ ²² ²³, Glu²⁵ ²⁹, Leu²⁸ ³¹, Lys²⁶³⁰]hPTHrP(1-34) NH₂; [Cha¹⁵, Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵, Glu²² ²⁵ ²⁹, Lys²³ ²⁵ ³⁰, Leu²⁸³¹]hPTHrP(1-34) NH₂; [Cha¹⁵, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁵, Aib³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵, Glu²² ²⁸ ²⁹, Leu²³ ³¹, Lys²⁶ ²⁸³⁰]hPTHrP(1-34)NH₂; [Cha¹⁵ ³⁰, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹,Lys²⁶]hPTHrP(1-34)NH₂; [Cha⁷ ⁸ ²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ⁸, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ²⁷³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ⁸ ²² ²³, Glu²⁵ ²⁹, Leu²⁸ ³¹, Lys²⁶ ³⁰] hPTHrP(1-34)NH₂; [Cha⁷ ⁸, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰] hPTHrP(1-34)NH₂;[Cha⁷ ⁸ , Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹, Lys²⁶ ³⁰]hPTHrP(1-34) NH₂; [Cha⁷⁸, Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰, Leu²⁸ ³¹]hPTHrP(1-34)NH₂; [Cha⁷ ⁸, Glu²² ²⁵²⁹, Leu²³ ²⁸ ³¹, Lys²⁶, Aib³⁰] hPTHrP(1-34)NH₂; [Cha⁷ ⁸, Glu²² ²⁵ ²⁹,Leu²³ ³¹, Lys²⁶ ²⁸ ³⁰]hPTHrP(1-34)NH₂; [Cha⁷ ⁸ ³⁰, Glu²² ²⁵ ²⁹, Leu²³ ²⁸³¹, Lys²⁶]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹ ²², Met⁸, Asn¹⁰, His¹⁴,Leu²³ ²⁸ ³¹, Glu²⁵ ²⁵, Lys²⁶ ³⁰]hPTHrP(1-34) NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹,Met⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ²⁷³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹, Met⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵²⁹, Leu²³ ³¹, Lys²⁶ ²⁸ ³⁰]hPTHrP(1-34)NH₂; Ser¹, Ile⁵, Cha⁷ ¹¹, Met⁸,Asn¹⁰, His¹⁴, Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰, Leu²⁸ ³¹]hPTHrP(1-34)NH₂; [Ser¹,Ile⁵, Cha⁷ ¹¹, Met⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹, Lys²⁶³⁰]hPTHrP(1-34) NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹, Met⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ , Aib³⁰] PTHrP(1-34)NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹ ²²²³, Met⁸, Asn¹⁰, His¹⁴, Glu²⁵ ²⁹, Leu²⁸ ³¹, Lys²⁶ ³⁰]hPTHrP(1-34) NH₂;[Ser¹, Ile⁵, Cha⁷ ¹¹ ¹⁵, Met⁸, Asn¹⁰, His¹⁴]hPTHrP(1-34)NH₂; [Ser¹,Ile⁵, Met⁸, Asn¹⁰, Leu¹¹, His¹⁴, Aib¹⁸]hPTHrP (1-34)NH₂; [Ser¹, Ile⁵,Met⁸, Asn¹⁰, Leu¹¹ ²⁸ ³¹, His¹⁴, Cha²² ²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Cha⁷ ¹¹, Met⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵ ²⁹, Leu²³²⁸ ³¹, Lys²⁶ ³⁰]hPTHrP (1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, His¹⁴,Cha¹⁵, Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰]hPTHrP (1-34)NH₂; [Ser¹, Ile⁵,Cha⁷ ⁸, Asn¹⁰, His¹⁴, Glu²² ²⁵ ²⁹, Leu²³ ²⁵ ³¹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂;[Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁴ ²⁶ ³⁰]hPTHrP(1-34)NH₂;[Aib²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹,Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹,Aib²⁶, Lys³⁰]hPTHrP (1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸, Lys²⁶ ³⁰ ³¹]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²³ ²⁸ ³¹, His¹⁴, Cha²²,Glu²⁵ ²⁹, Lys²⁸ ³⁰] hPTHrP(2-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²⁸³¹, His¹⁴, Glu²² ²⁵ ²⁹, Lys²³ ²⁶ ³⁰]PTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸,Asn¹⁰, Leu¹¹ ²³ ²⁸ ³¹, His¹⁴, Glu²² ²⁵ ²⁹, Lys²⁶ ²⁷ ³⁰] hPTHrP(1-34)NH₂;[Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²³ ³¹, His¹⁴, Glu²² ²⁵ ²⁹, Lys²⁵ ²⁸ ³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²³ ²⁸ ³¹, His¹⁴, Glu²²²⁵, Aib²⁹, Lys²⁶ ³⁰] hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu¹¹ ²³²⁸ ³¹, His¹⁴, Glu²² ²⁵ ²⁹, Lys²⁵, Aib³⁰] hPTHrP(1-34)NH₂; or [Ser¹,Ile⁵, Met⁸]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Ahc²³, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁶ Leu²³ ²⁸ ³¹, Lys²⁶ ³⁰, Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ Leu²³ ²⁸, Lys²⁶ ³⁰, Aib²⁹,Ahc³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ Cha²³, Lys²⁶ ³⁰, Leu²⁸ ³¹,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ Cha²³, Lys²⁶ ³⁰, Leu²⁸,Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ Cha²³, Lys²⁶ ³⁰, Aib²⁹]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰, Aib²⁹]hPTHrP(1-34)NH₂;[Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁶, Aib²⁹, Ahc³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵,Cha²³, Lys²⁶ ³⁰, Aib²⁹, Leu³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹,Ahc²⁴, Lys²⁶ ³⁰, Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ³¹, Lys²⁶ ³⁰,Ahc²⁸, Aib²⁹]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Lys²⁸, Aib²⁹ ³⁰]hPTHrP (1-34)NH₂; [Aib²² ²⁹, Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁸ ²⁹, Lys³⁰]hPTHrP(1-34)NH₂; [Cha²²,Ahc²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰, Leu²⁸ ³¹]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸³¹, Ahc²⁴, Glu²⁵ ²⁹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹,Glu²⁵ ²⁹, Lys²⁶ ³⁰, Ahc²⁷]hPThrP(1-34)NH₂; [Cha²², Leu²³ ³¹, Glu²⁵ ²⁹,Lys²⁶ ³⁰, Ahc²⁸]hPTHrP(1-34)NH₂; [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶,Leu²⁸, Ahc³⁰]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Leu³¹]hPTHrP (1-34)NH₂; [Cha²², Leu²³ ²⁸, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Ahc³¹]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Leu³¹]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰,Leu²⁸]hPTHrP(1-34)NH₂; [Cha²² ²³, Glu²⁵ ²⁹, Lys²⁶ ³⁰] hPTHrP(1-34)NH₂;[Glu²², Leu²³ ²⁸ ³¹, Aib²⁵ ²⁹, Lys²⁶ ³⁰]hPTHrP(1-34) NH₂; [Glu²² ²⁹,Ahc²³, Aib²⁵, Lys²⁶ ³⁰, Leu²⁸ ³⁰, Leu²⁸ ³¹]hPTHrP(1-34)NH₂; [Ahc²²,Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁶ ³⁰, Glu²⁹] hPTHrP(1-34)NH₂; [Aib²² ²⁵, Leu²³²⁸ ³¹, Lys²⁶ ³⁰, Glu²⁹]hPTHrP (1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Ahc²⁴,Aib²⁵, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵ ²⁶,Lys³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁵ ³⁰, Ahc²⁷]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ³¹, Aib²⁵, Lys²⁵ ³⁰,Ahc²⁸]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁹, Leu²³ ²⁸, Aib²⁵, Lys²⁶ ³⁰,Ahc³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵ ³⁰, Lys²⁶]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Leu²³ ²⁸ ³¹, Aib²⁵, Lys²⁶,Ahc³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Cha²³, Aib²⁵, Lys²⁶ ³⁰, Leu²⁸³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Cha²³, Aib²⁵, Lys²⁶ ³⁰,Leu³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Cha²³, Aib²⁵, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁹, Cha²³, Aib²⁵, Lys²⁶ ³⁰, Leu²⁸]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Cha²³, Lys²⁶, Leu²⁸ ³¹, Aib³⁰] hPTHrP (1-34)NH₂;[Glu²² ²⁵ ²⁹, Cha²³, Lys²⁶, Aib³⁰, Leu³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹,Cha²³, Lys²⁶, Aib³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Cha²³; Lys²⁶, Leu²⁸,Aib³⁰]hPTHrP(1-34)Nh₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁵, Ahc²⁷, Aib³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Ahc²⁴, Lys²⁶, Aib³⁰]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶, Aib³⁰]hPTHrP(1-34)NH₂;[Aib²² ³⁰, Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶] hPTHrP(1-34)NH₂; [Gky²² ²⁸,Lys²⁶ ³⁰ ³¹, Aib²⁹]hPTHrP(1-34) NH₂; [Cha²², Leu²³ ²⁸, Glu²⁵ ²⁹, Lys²⁶³⁰ ³¹]hPTHrP(1-34)NH₂; [Ahc²², Leu²³ ²⁸, Glu²⁵ ²⁹, Lys²⁵ ³⁰ ³¹]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸, Lys²⁶ ³⁰ ³¹, Ahc³⁰]hPTHrP(1-34)NH₂; [Glu²² ²⁵ ²⁹, Leu²³ ²⁸ ³¹, Lys²⁶, Ahc³⁰]hPTHrP(1-34)NH₂;[Ahc²², Leu²³ ²⁸ ³¹, Glu²⁵ ²⁹, Lys²⁶ ³⁰]hPTHrP (1-34)NH₂; [Glu²² ²⁵ ²⁹,Leu²³ ²⁸, Lys²⁶ ³⁰ ³¹, Ahc²⁷]hPTHrP(1-34)NH₂.

In another aspect, the present invention is directed to a method oftreating osteoporosis in a patient in need thereof, which comprisesadministering to said patient a compound of formula (I), (II), (III),(IV) or (V) or a pharmaceutically acceptable salt thereof, as definedhereinabove.

In another aspect, the present invention is directed to a method oftreating osteoporosis in a patient in need thereof, which comprisesadministering to said patient a combination of a bisphosphonate orcalcitonin and a compound of formula (I), (II), (III), (IV) or (V) or apharmaceutically acceptable salt thereof, as defined hereinabove.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a compound of formula (I), (II), (III), (IV) or(V) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or diluent.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a compound of formula (I), (II), (III), (IV) or(V) or a pharmaceutically acceptable salt thereof as definedhereinabove, a bisphosphonate or calcitonin and a pharmaceuticallyacceptable carrier or diluent.

In another aspect, the present invention is directed to a method oftreating osteoporosis in a patient in need thereof, which comprisesadministering to said patient a peptide of the formula [Glu²² ²⁵, Leu²³²⁸ ³¹, Aib²⁹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂ or a pharmaceutically acceptablesalt thereof.

In another aspect, the present invention is directed to a method oftreating osteoporosis in a patient in need thereof, which comprisesadministering to said patient a combination of a bisphosphonate orcalcitonin and a peptide of the formula [Glu²² ²⁵, Leu²³ ²⁸ ³¹, Aib²⁹,Lys²⁸ ³⁰]hPTHrP(1-34)NH₂ or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a peptide of the formula [Glu²² ²⁵, Leu²³ ²⁸ ³¹,Aib²⁹, Lys²⁶ ³⁰]hPTHrP(1-34)NH₂ or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a peptide of the formula [Glu²² ²⁵, Leu²³ ²⁸ ³¹,Aib²⁹, Lys²⁶ ³⁰]hPTHrP(1-34(NH₂ or a pharmaceutically acceptable saltthereof, a bisphosphonate or calcitonin, and a pharmaceuticallyacceptable carrier or diluent.

In another aspect, the present invention is directed to a method oftreating osteoporosis inn a patient in need thereof, which comprisesadministering to said patient a peptide of the formula (VI):

wherein

-   A₁ is Ala, Ser, or Dap;-   A₃is Ser or Aib;-   A₅ is His, Ile, Acc, or Cha;-   A₇ is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which    X is OH, a halogen, or CH₃;-   A₈ is Leu, Met, Acc, or Cha;-   A₁₀ is Asp or Asn;-   A₁₁ is Lys, Leu, Cha, Acc, Phe, or β-Nal;-   A₁₂ is Gly, Acc, or Aib;-   A₁₄ is Ser or His;-   A₁₅ is Ile, Acc, or Cha;-   A₁₆ is Gln or Aib;-   A₁₇ is Asp or Aib;-   A₁₈ is Leu, Aib, Acc, or Cha;-   A₁₉ is Arg or Aib;-   A₂₂ is Phe, Glu, Aib, Acc, or Cha;-   A₂₃ is Phe, Leu, Lys, Acc, or Cha;-   A₂₄ is Leu, Lys, Acc, or Cha;-   A₂₅ is His, Lys, Aib, Acc, or Glu;-   A₂₆ is His, Aib, Acc, or Lys;-   A₂₇ is Leu, Lys, Acc, or Cha;-   a₂₈ is Ile, Leu, Lys, Acc, or Cha;-   A₂₉ is Ala, Glu, Acc, or Aib;-   A₃₀ is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;-   A₃₁ is Ile, Leu, Cha, Lys, Acc, or deleted;-   A₃₂ is His or deleted;-   A₃₃ is Thr or deleted;-   A₃₄ is Ala or deleted;    each of R₁ and R₂ is, independently, H, C₁₋₁₂ alkanyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂, hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; or one and only one of R₁ and R₂ is COE₁ in    which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀    phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂    hydroxyalkenyl, C₇₋₂₀ hydroxyphenylalkyl, or C₁₁₋₂₀    hydroxynaphthylalkyl; and-   R₃ is OH, NH₂, C₁₋₁₂ alkoxy, or NH—Y—CH₂—Z in which Y is a C₁₋₁₂    hydrocarbon moiety and Z is H, OH, CO₂H or CONH₂;

provided that at least one of A₅, A₇, A₈, A₁₁, A₁₂, A₁₅, A₁₈, A₂₂, A₂₃,A₂₄, A₂₅, A₂₆, A₂₇, A₂₈, A₂₉, A₃₀, or A₃₁ is Acc; or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention is directed to a method oftreating osteoporosis in a patient in need thereof, which comprisesadministering to said patient a combination of a bisphosphonate orcalcitonin and a peptide of formula (VI), as defined hereinabove.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a peptide of formula (VI), as defined hereinabove.

In another aspect, the present invention is directed to a pharmaceuticalcomposition comprising a bisphosphonate or calcitonin, apharmaceutically acceptable carrier or diluent, and a peptide of formula(VI), as defined hereinabove.

With the exception of the N-terminal amino acid, all abbreviations (e.g.Ala or A₁) of amino acids in this disclosure stand for the structure of—NH—CH(R)—CO—, wherein R is a side chain of an amino acid (e.g. CH₃ forAla). For the N-terminal amino acid, the abbreviation stands for thestructure of ═N—CH(R)—CO—, wherein R is a side chain of an amino acid.β-Nal, Nle, Dap, Cha, Nva, Amp, Pal, Ahc, and Aib are the abbreviationsof the following α-amino acids; β-(2-naphthyl)alanine, norleucine,α,β-diaminopropionic acid, cyclohexylalanine, norvaline,4-amino-phenylalanine, β-(3-pyridinyl)alanine.1-amino-1-cyclo-hexanecarboxylic acid, and α-aminoisubutyric acid,respectively. What is meant by Acc is an amino acid selected from thegroup of 1-amino-1-cyclopropanecarboxylic acid:

-   1-amino-1-cyclobutanecarboxylic acid;-   1-amino-1-cyclopentanecarboxylic acid;-   1-amino-1-cyclohexanecarboxylic acid;-   1-amino-1-cycloheptanecarboxylic acid;-   1-amino-1-cyclooctanecarboxylic acid;-   1-amino-1cyclononanecarboxylic acid. In the above formula,    hydroxyalkyl, hydroxyphenyl-alkyl, and hydroxynaphthylalkyl may    contain 1-4 hydroxy substituents. Also, COE₁ stands for —C═O.E₁.    Examples of —C═O.E₁ include, but are not limited to, acetyl and    phenylpropionyl.

A peptide of this invention is also denoted herein by another format,e.g,, [Ahc⁷ ¹¹]hPTH(1-34)NH₂, with the substituted amino acids from thenatural sequence placed between the second set of brackets (e.g., Ahc⁷for Leu⁷, and Ahc¹¹ for Leu¹¹ in hPTH). The abbreviation hPTH stands forhuman PTH, hPTHrP for human PTHrP, rPTH for rat PTH, and bPTH for bovinePTH. The numbers between the parentheses refer to the number of aminoacids present in the peptide (e.g., hPTH(1-34) is amino acids 1 through34 of the peptide sequence for human PTH). The sequences for hPTH(1-34),hPTHrP(1-34), bPTH(1-34), and rPTH(1-34) are listed in Nissenson, etal., Receptor, 3:193 (1993). The designation “NH₂” in PTH(1-34)NH₂indicates that the C-terminus of the peptide is amidated. PTH(1-34), onthe other hand, has a free acid C-terminus.

Each of the peptides of the invention is capable of stimulating thegrowth of bone in a subject (i.e., a mammal such as a human patient).Thus, it is useful in the treatment of osteoporosis and bone fractureswhen administered alone or concurrently with antiresorptive therapy,e.g., bisphosphonates and calcitonin.

The peptides of this invention can be provided in the form ofpharmaceutically acceptable salts. Examples of such salts include, butare not limited to, those formed with organic acids (e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic,methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids(e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), andpolymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic,polyglycolic, or copolymers of polylactic-glycolic acids).

A therapeutically effective amount of a peptide of this invention and apharmaceutically acceptable carrier substance (e.g., magnesiumcarbonate, lactose, or a phospholipid with which the therapeuticcompound can form a micelle) together form a therapeutic composition(e.g., a pill, tablet, capsule, or liquid) for administration (e.g.,orally, intravenously, transdermally, pulmonarily, vaginally,subcutaneously, nasally, iontophoretically, or by intratracheally) to asubject. The pill, tablet, or capsule that is to be administered orallycan be coated with a substance for protecting the active compositionfrom the gastric acid or testinal enzymes in the stomach for a period oftime sufficient to allow it to pass undigested into the small intestine.The therapeutic composition can also be in the form of a biodegradableor nonbiodegradable sustained release formulation for subcutaneous orintramuscular administration. See, e.g., U.S. Pat. Nos. 3,773,919 and4,767,628 and PCT Application No. WO 94/15587. Continuous administrationcan also be achieved using an implantable or external pump (e.g.,INFUSAID™ pump). The administration can also be conductedintermittently, e.g., single daily injection, or continuously at a lowdose, e.g., sustained release formulation.

The dose of a peptide of the present invention for treating theabove-mentioned diseases or disorders varies depending upon the mannerof administration, the age and the body weight of the subject, and thecondition of the subject to be treated, and ultimately will be decidedby the attending physician or veterinarian.

Also contemplated within the scope of this invention is a peptidecovered by the above generic formula for use in treating diseases ordisorders associated with deficiency in bone growth or the like, e.g.,osteoporosis or fractures.

Other features and advantages of the present invention will be apparentfrom the detailed description and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

Based on the description herein, the present invention can be utilizedto its fullest extent. The following specific examples are to beconstrued as merely illustrative, and should not be construed as alimitation of the remainder of the disclosure in any way whatsoever.Further, all publications cited herein are incorporated by reference.

Structure

PTH(1-34) and PTHrP(1-34) have been reported to have two amphophilicalpha helical domains. See, e.g., Barden, et al., Biochem., 32:7126(1992). The first “-helix is formed between amino acid residues 4through 13, while the second “-helix is formed between amino acidresidues 21 through 29. Some peptides of this invention contain thesubstitution of Acc for one or more residues within or near these tworegions of PTH(1-34) and PTHrP(1-34), e.g., Ahc⁷ and Ahc¹¹ within thefirst “-helix or Ahc²⁷ and Ahc²⁸ within the second “-helix; or Cha⁷ andCha¹¹ within the first α-helix or Cha²⁷ and Cha²⁸ within the secondα-helix.

Synthesis

The peptides of the invention can be prepared by standard solid phasesynthesis. See, e.g., Stewart, J. M., et al., Solid Phase Synthesis(Pierce Chemical Co., 2d ed. 1984) The following is a description of how[Glu²² ²⁵, Leu²³ ²⁸, Lys²⁶ ³⁰, Aib²⁹, Ahc³¹]hPTH(1-34)NH₂ was prepared.Other peptides of the invention can be prepared in an analogous mannerby a person of ordinary skill in the art.

1-[N-tert-Butoxycarbonyl-amino]-1-cyclohexane-carboxylic acid(Boc-Ahc—OH) was synthesized as follows:

19.1 g (0.133 mol) of 1amino-1cyclohexanecarboxylic acid (AcrosOrganics, Fisher Scientific, Pittsburgh, Pa.) was dissolved in 200 ml ofdioxane and 100 ml of water. To it was added 67 mg of 2N NaOH. Thesolution was cooled in an ice-water bath. 32.0 g (0.147 mol) ofdi-tert-butyl-dicarbonate was added to this solution. The reactionmixture was stirred overnight at room temperature. Dioxane was thenremoved under reduced pressure. 200 ml of ethyl acetate was added to theremaining aqueous solution. The mixture was cooled in an ice-water bath.The pH of the aqueous layer was adjusted to about 3 by adding 4N HCl.The organic layer was separated. The aqueous layer was extracted withethyl acetate (1×100 ml). Two organic layers were combined and washedwith water (2×150 ml), dried over anhydrous MgSO₄, filtered, andconcentrated to dryness under reduced pressure. The residue wasrecrystallized in ethyl acetate/hexanes. 9.2 g of a pure product wasobtained. 29% yield. Other protected Acc amino acids can be prepared inan analogous manner by a person or ordinary skill in the art.

The peptide was synthesized on an Applied Biosystems (Foster City,Calif.) model 430A peptide synthesizer which was modified to doaccelerated Boc-chemistry solid phase peptide synthesis. See Schnoize,et al., Int. J. Peptide Protein Res., 90:180 (1992).4-Methylbenz-hydrylamine (MBHA) resin (Peninsula, Belmont, Calif.) withthe substitution of 0.93 mmol/g was used. The Boc amino acis (Bachem,Calif., Torrance, Calif.; Nova Biochem., LaJolla, Calif.) were used withthe following side chain protection. Boc-Ala—OH, Boc-Arg(Tos)—OH,Boc-Asp(OcHex)—OH, Boc-Glu(OcHex)—OH, Boc-His(DNP)—OH, Boc-Val—OH,Boc-Leu—OH, Boc-Gly—OH, Boc-Gln—OH, Boc-IIe—OH, Boc-Lys(2ClZ)—OH,Boc-Ahc—OH, Boc-Thr(Bzl)—OH, Boc-Ser(Bzl)—OH; and Boc-Aib—OH. Thesynthesis was carried out on a 0.14 mmol scale. The Boc groups wereremoved by treatment with 100% TFA for 2×1 min. Boc amino acids (2.5mmol) were pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 lmL of DMF and were coupled without prior neutralization of thepeptide-resin TFA salt. Coupling times were 5 min except for theBoc-Aib—OH, and its following residue Boc-Leu—OH, and Boc-Ahc—OH, andits following residue Boc-Lys(2 Clz)—OH, wherein the coupling times forthese four residues were 2 hrs.

At the end of the assembly of the peptide chain, the resin was treatedwith a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. toremove the DNP group on the His side chain. The N-terminal Boc group wasthen removed by treatment with 100% TFA for 2×2 min. Thepartially-deproteted peptide-resin was washed with DMF and DCM and driedunder reduced pressure. The final cleavage was done by stirring thepeptide-resin in 10 mL of HF containing 1 mL of anisole anddithiothreitol (24 mg) at OEC for 75 min. HF was removed by a flow ofnitrogen. The residue was washed with ether (6×10 mL) and extracted with4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on areversed-phase preparative high pressure liquid chromatography (HPLC)using a reversed phase VYDAC™ C₁₈ column (Nest Group, Southborough,Mass.). The column was eluted with a linear gradient (10% to 45% ofsolution B over 130 min.) at a flow rate of 10 mL/min (Solution A=0.1%aqueous TFA. Solution B=acetonitrile containing 0.1% of TFA). Fractionswere collected and checked on analytical HPLC. Those containing pureproduct were combined and lyophilized to dryness. 85 mg of a white solidwas obtained. Purity was >99% based on analytical HPLC analysis.Electro-spray mass spectrometer analysis gave the molecular weight at3972.4 (in agreement with the calculated molecular weight of 3972.7).

The synthesis and purification of [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰,Ahc²⁷, Aib²⁹]hPTHrP(1-34)NH₂ was carried out in the same manner as theabove synthesis of [Glu²² ²⁵, Leu²³ ²⁸, Lys²⁶ ³⁰, Aib²⁹,Ahc³¹]hPTHrP(1-34)NH₂. The protected amino acid Boc-Cha—OH was purchasedfrom, Bachem, Calif. The purity of the final product was >99%, and theelectron-spray mass spectrometer gave the molecular weight at 3997.2(calculated molecular weight is 3996.8).

The following is a description of how [Aib³⁴]hPTH(1-34)NH₂ was prepared.The peptide, [Aib³⁴]hPTH(1-34)NH₂, was synthesized on an AppiledBiosystems (Foster City, Calif.) model 430A peptide synthesizer whichwas modified to do accelerated Boc-chemistry solid phase peptidesynthesis. See Schnoize, et al., Int. J. Peptide Protein Res,. 90:180(1992). 4-Methylbenz-hydrylamine (MBHA) resin (Peninsula, Belmont,Calif.) with the substitution of 0.93 mmol/g was used. The Boc aminoacids (Bachem, Calif., Torrance, Calif.; Nova Biochem., Lajolla, Calif.)were used with the following side chain protection: Boc-Arg(Tos)—OH,Boc-Asp(OcHxl)—OH, Boc-Asn(Xan)—OH, Boc-Glu(OcHxl)—OH, Boc-His(DNP)—OH,Boc-Asn—GH, Boc-Val—OH, Boc-Leu—OH, Boc-Ser—OH, Boc-Gly—OH, Boc-Met—OH,Boc-Gln—OH, Boc-Ile—OH. Boc-Lys(2ClZ)—OH, Boc-Ser(Bzl)—OH, andBoc-Trp(Fm)—OH. The synthesis was carried out on a 0.14 mmol scale. TheBoc groups were removed by treatment with 100% TFA for 2×1 min. Boxamino acids (2.5 mmol) were pre-activated with HBTU (2.1 mmol) and DIEA(1.0 mL) n 4 mL of DMF and were coupled without prior neutralization ofthe peptide-resin TFA salt. Coupling times were 5 min except for theBoc-Aib—OH and the following residue, Boc-Asn(Xan)—OH, wherein thecoupling times were 20 min.

At the end of the assembly of the peptide chain, the resin was treatedwith a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. toremove the DNP group on the His side chain. The N-terminal Boc group wasthen removed by treatment with 100% TFA for 2×2 min. Afterneutralization of the peptide-resin with 10% DIEA in DMF (1×1 min.), theformyl group on the side chain of Trp was removed by treatment with asolution of 15% ethanolamine/15% water/70% DMF for 2×30 min. Thepartially-deprotected peptide-resin was washed with DMF and DCM anddried under reduced pressure. The final cleavage was done by stirringthe peptide-resin in 10 mL of HF containing 1 mL of anisole at 0° C. for75 min. HF was removed by a flow of nitrogen. The residue was washedwith ether (6×10 ) mL) and extracted with 4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on areversed-phase preparative high pressure liquid chromatography (HPLC)using a reversed phase VYDAC™ C₁₈ column (Nest Group, Southborough,Mass.). The column was eluted with a linear gradient (10% to 45% ofsolution B over 130 min.) at a flow rate of 10 mL/min (Solution A=0.1%aqueous TFA; Solution B=acetonitrile containing 0.1% of TFA). Fractionswere collected and checked on analytic HPLC. Those containing pureproduct were combined and lyophilized to dryness. 62.3 mg of a whitesolid was obtained. Purity was >99% based on analytical HPLC analysis.Electro-spray mass spectrometer analysis gave the molecular weight at4054.7 (in agreement with the calculated molecular weight of 4054.7).

The synthesis and purification of [Cha⁷ ¹¹]hPTH(1-34)NH₂ was carried outin the same manner as the above synthesis of [Aib³⁴]hPTH(1-34)NH₂. Theprotected amino acid Boc-Cha—OH was purchased from Bachem, Calif. Thepurity of the final product was >98%, and the electron-spray massspectrometer gave the molecular weight at 4197.0 (calculated molecularweight is 4196.9).

The following is a description of how [Glu²² ²⁵, Leu²³ ²⁸, Lys²⁶ ³⁰,Aib²⁹, Ahc³¹]hPTH(1-34)NH₂ was prepared. Other peptides of the inventioncan be prepared in an analogous manner by a person of ordinary skill inthe art.

1-[N-tert-Butoxycarbonyl-amino]-1-cyclohexane-carboxylic acid(Boc-Ahc—OH) was synthesized as follows.

19.1 g (0.133 mol) of 1-amino-1-cyclohexanecarboxylic acid (AcrosOrganics, Fisher Scientific, Pittsburgh, Pa.) was dissolved in 200 ml ofdioxane and 100 ml of water. To it was added 67 mg of 2N NaOH. Thesolution was cooled in an ice-water bath. 32.0 g (0.147 mol) ofdi-tert-butyl-dicarbonate was added to this solution. The reactionmixture was stirred overnight at room temperature. Dioxane was thenremoved under reduced pressure. 200 ml of ethyl acetate was added to theremaining aqueous solution. The mixture was cooled in an ice-water bath.The pH of the aqueous layer was adjusted to about 3 by adding 4N HCl.The organic layer was separated. The aqueous layer was extracted withethyl acetate (1×100 ml). Two organic layers were combined and washedwith water (2×150 ml), dried over anhydrous MgSO₄, filtered, andconcentrated to dryness under reduced pressure. The residue wasrecrystallized inn ethyl acetate/hexanes. 9.2 g of a pure product wasobtained. 29% yield. Other protected Acc amino acids can be prepared inan analogous manner by a person or ordinary skill in the art.

The peptide was synthesized on an Applied Biosystems (Foster City,Calif.) model 430A peptide synthesizer which was modified to doaccelerated Boc-chemistry solid phase peptide synthesis. See Schnoize,et al., Int. J. Peptide Protein Res., 90:180 (1992).4-Methylbenz-hydrylamine (MBHA) resin (Peninsula, Belmont, Calif.) withthe substitution of 0.93 mmol/g was used. The Boc amino acids (Bachem,Calif., Torrance, Calif.; Nova Biochem., LaJolla, Calif.) were used withthe following side chain protection: Boc-Ala—OH, Boc-Arg(Tos)—OH,Boc-Asp(OcHex)—OH, Boc-Glu(OcHex)—OH, Box-His(DNP)—OH, Boc-Val—OH,Boc-Leu—OH, Boc-Gly—OH, Boc-Gln—OH, Boc-Lys(2ClZ)—OH, Boc-Ahc—OH,Boc-Thr(Bzl)—OH, Box-Ser(Bzl)—OH; and Box-Aib—OH. The synthesis wascarried out on a 0.14 mmol scale. The Boc groups were removed bytreatment with 100% TFA for 2×1 min. Boc amino acids (2.5 mmol) werepre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF andwere coupled without prior neutralization of the peptide-resin TFA salt.Coupling times were 5 min except for the Boc-Aib—OH, and its followingresidue Boc-Leu—OH and Boc-Ahc—OH, and its following residueBoc-Lys(2Clz)—OH, wherein the coupling times for these four residueswere 2 hours.

At the end of the assembly of the peptide chain, the resin was treatedwith a solution of 20% mercaptoethanol/10% DIEA in DMF for 2×30 min. toremove the DNP group on the His side chain. The N-terminal Boc group wasthen removed by treatment with 100% TFA for 2×2 min. Thepartially-deprotected peptide-resin was washed with DMF and DCM anddried under reduced pressure. The final cleavage was done by stirringthe peptide-resin in 10 mL of HF containing 1 mL of anisole anddithiothreitol (24 mg) at 0° C. for 75 min. HF was removed by a flow ofnitrogen. The residue was washed with ether (6×10 mL) and extracted with4N HOAc (6×10 mL).

The peptide mixture in the aqueous extract was purified on areversed-phase preparative high pressure liquid chromatography (HPLC)using a reversed phase VYDAC™ C₁₈ column (Nest Group, Southborough,Mass.). The column was eluted with a linear gradient (10% to 45% ofsolution B over 130 min.) at a flow rate of 10 mL/min (Solution A=0.1%aqueous TFA: Solution B=acetonitrile containing 0.1% of TFA). Fractionswere collected and checked on analytical HPLC. Those containing pureproduct were combined and lyophilized to dryness. 85 mg of a white solidwas obtained. Purity was >99% based on analytical HPLC analysis.Electro-spray mass spectrometer analysis gave the molecular weight at3972.4 (in agreement with the calculated molecular weight of 3972.7).

The synthesis and purification of [Cha²², Leu²³ ²⁸ ³¹, Glu²⁵, Lys²⁶ ³⁰,Ahc²⁷, Aib²⁹]hPTHrP(1-34)NH₂ was carried out in the same manner as theabove synthesis of [Glu²² ²⁵, Leu²³ ²⁸, Lys²⁶ ³⁰, Aib²⁹,Ahc³¹]hPTHrP(1-34)NH₂. The protected amino acid Boc-Cha—OH was purchasedfrom Bachem, Calif. The purity of the final product was >99%, and theelectron-spray mass spectrometer gave the molecular weight at 3997.2(calculated molecular weight is 3996.8).

The full names for the abbreviations used above are as follows: Boc fort-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan forxanthyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMFfor dimethylformamide, DCM for dichloromethane. HBTU for2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, DIEA for diisopropylethylamine, HOAc for aceticacid, TFA for trifluoroacetic acid, 2ClZ for 2-chlorobenzyloxycarbonyl,and OcHex for O-cyclohexyl.

The substituents R₁ and R₂ of the above generic formula may be attachedto the free amine of the N-terminal amino acid by standard methods knownin the art. For example, alkyl groups, e.g., C₁₋₁₂ alkyl, may beattached using reductive alkylation. Hydroxyalkyl groups, e.g., C₁₋₁₂hydroxyalkyl, may also be attached using reductive alkylation whereinthe free hnydroxy group is protected with a t-butyl ester. Acyl groups,e.g., may be attached by coupling the free acid, e.g., E₁COOH, to thefree amine of the N-terminal amino acid by mixing the completed resinwith 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for one hour and cyclingthe resulting resin through steps (a) to (f) in the above wash program.If the free acid contains a free hydroxy group, e.g.,p-hydroxyphenylpropionic acid, then the coupling should be performedwith an additional 3 molar equivalents of HOBT.

Other peptides of this invention can be prepared in an analogous mannerby a person of ordinary skill in the art.

Functional Assays

A. Binding to PTH Receptor

The peptides of the invention were tested for their ability to bind tothe PTH receptor present on SaOS-2 (human osteosarcoma cells). SaOS-2cells (American Type Culture Collection, Rockville, Md.; ATCC #HTB 85)were maintained in RPMI 1640 medium (Sigma, St. Louis, Mo.) supplementedwith 10% fetal bovine serum (FBS) and 2 mM glutamine at 3EC in ahumidified atmosphere of 5% CO₂ in air. The medium was changed everythree or four days, and the cells were subcultured every week bytrypsinization.

SaOS-2 cells were maintained for four days until they had reachedconfluence. The medium was replaced with 5% FBS in RPMI 1640 medium andincubated for 2 hrs at room temperature with 10×10⁴ cpm mono-¹²⁵l-[Nle⁸¹⁸, Tyr³⁴(3-¹²⁵l)] bPTH(1-34)NH₂ in the presence of a competing peptidesof the invention at various concentrations between 10⁻¹¹ M to 10⁻⁴ M.The cells were washed four times with ice-cold PBS and lysed with 0.1 MNaOH, and the radioactivity associated with the cells was counted in ascintillation counter. Synthesis of mono-¹²⁵l-[Nle⁸ ¹⁸,Tyr³⁴(3-¹²⁵l)]bPTH(1-34)NH₂ was carried out as described in Goldman, M.E., el al., Endocrinol., 123:1468 (1988).

The binding assay was conducted with various peptides of the inventionand the Kd value (half maximal inhibition of binding of mono-¹²⁵l-[Nle⁸¹⁸, Tyr³⁴(3-¹²⁵l)]bPTH(1-34)NH₂) for each peptide was calculated.

As shown in Table I, all of the tested peptides had a high bindingaffinity for the PTH receptor on the SaOS-2 cell.

B. Stimulation of Adenylate Cyclase Activity

The ability of the peptides of the invention to induce a biologicalresponse in SaOS-2 cells were measured. More specifically, anystimulation of the adenylate cyclase was determined by measuring thelevel of synthesis of cAMP (adenosine 3′, 5′-monophosphate) as describedpreviously in Rodan, et al., J. Clin. Invest. 72; 1511 (1983) andGoldman, et al., Endocrinol., 123:1468 (1988). Confluent SAOS-2 cells in24 wells plates were incubated with 0.5.Cl [³H]adenine (26.9 Cl/mmol,New England Nuclear, Boston, Mass.) in fresh medium at 37EC for 2 hrs,and washed twice with Hank's balanced salt solution (Gibco,Gaithersburg, Md.). The cells were treated with 1 mM IBMX[isobutylmethyl-xanthine, Sigma, St. Louis, Mo.] in fresh medium for 15min, and the peptides of the invention were added to the medium toincubate for 5 min. The reaction was stopped by the addition of 1.2 Mtrichloroacetic acid (TCA) (Sigma, St. Louis, Mo.) followed by sampleneutralizaton with 4N KOH. cAMP was isolated by the two-columnchromatographic method (Salmon, et al., 1974, Anal. Biochem. 58, 541).The radioactivity was counted in a scintillation counter (LiquidScintillation Counter 2200CA, PACKARD, Downers Grove, Ill.).

The respective EC₅₀ values (half maximal stimulation of adenylatecyclase) for the tested peptides were calculated and shown in Table I.All tested peptides were found to be potent stimulators of adenylatecyclase activity, which is a biochemical pathway indicative as aproximal signal for osteoblast proliferation (e.g., bone growth). TABLEI EC₅₀ PEPTIDE Kd (μM) (nM) [Cha^(7, 11)]hPTH(1-34)NH₂ 0.01 0.6[Cha²³]hPTH(1-34)NH₂ 0.2 20 [Cha²⁴]hPTH(1-34)NH₂ 0.1 10 [Nle^(8, 18),Cha²²]hPTH(1-34)NH₂; 0.05 2 [Cha²⁸]hPTH(1-34)NH₂ 0.05 2.5[Cha³¹]hPTH(1-34)NH₂ 0.03 4 [Aib¹⁶]hPTH(1-34)NH₂; 0.004 0.7[Aib¹⁹]hPTH(1-34)NH₂; 0.005 0.6 [Aib³⁴]hPTH(1-34)NH₂; 0.007 3[Nle³¹]hPTH(1-34)NH₂; 0.004 0.7 [hArg²⁷]hPTH(1-34)NH₂ 0.007 1 [Dap,Nle^(8, 18), Tyr³⁴]hPTH(1-34)NH₂; 0.150 10 [Cha^(24, 28, 31),Lys³⁰]hPTH(1-34)NH₂; 0.5 7 [Cha^(7, 11), Nle^(8, 18),Tyr³⁴]hPTH(1-34)NH₂ 0.006 0.6 [Cha^(7, 11), Nle^(8, 18), Aib^(16, 19),Tyr³⁴]hPTH (1-34)NH₂ 0.005 1.5 [Cha^(7, 11), Nle^(8, 18, 31),Aib^(16, 19), Tyr³⁴]hPTH(1-34)NH₂ 0.04 4 [Cha¹¹]hPTH(1-34)NH₂ 0.005 2[Cha^(28, 31)]hPTH(1-34)NH₂ 0.06 7 [Cha^(7, 11), Nle^(8, 18),Aib³⁴]hPTH(1-34)NH₂ 0.03 1.5 [Cha¹⁸]hPTH(1-34)NH₂ 0.005 1.3 [Cha^(7,11),Aib¹⁹]hPTH(1-34)NH₂ 0.007 0.5 [Cha^(7,11), Aib¹⁶]hPTH(1-34)NH₂ 0.004 1.1[Aib^(15, 19)]hPTH(1-34)NH₂ 0.004 0.6 [Aib¹²]hPTH(1-34)NH₂ 0.005 2[Aib³]hPTH(1-34)NH₂ 0.004 1.1 [Cha^(7,11), Aib¹⁹, Lys³⁵]hPTH(1-34)NH₂0.004 2 [Cha⁷]hPTH(1-34)NH₂ 0.02 2.3 [Cha^(24,28, 31)]hPTH(1-34)NH₂ 1.030 [Aib¹⁷]hPTH(1-34) 0.05 3 [Cha^(7,11,15)]hPTH(1-34) 0.01 1.4

TABLE II Kd EC₅₀ PEPTIDE (μM) (nM) [Glu^(22,25), Leu^(23,28),Lys^(26,30), Aib²⁹, 0.200 3.7 Ahc³¹]hPTHrP(1-34)NH₂ [Glu^(22,25), Ahc²³,Lys^(26,30), Leu^(28,31), 0.070 3.9 Aib²⁹]hPTHrP(1-34)NH₂ [Glu^(22,25),Leu^(23,28,31), Lys^(26,30), Ahc²⁷, 0.230 3.0 Aib²⁹]hPTHrP(1-34)NH₂[Glu^(22,25,29), Leu^(23,28,31), Lys²⁶, 0.230 20 Ahc³⁰]hPTHrP(1-34)NH₂[Cha²², Leu^(23,28,31), Glu²⁵, Lys^(26,30), 0.060 2.0 Ahc²⁷,Aib²⁹]hPTHrP(1-34)NH₂ [Glu^(22,25), Leu^(23,28,31), Ahc²⁴, Lys^(26,30),0.006 0.5 Aib²⁹]hPTHrP(1-34)NH₂ [Glu^(22,29), Leu^(23,28,31), Aib²⁹,Lys^(26,30), 5 Ahc²⁷]hPTHrP(1-34)NH₂ [Glu²², Leu^(23,28,31),Aib^(25,29), Lys^(26,30), 2 Ahc²⁷]hPTHrP(1-34)NH₂ [Ahe²²,Leu^(23,28,31), Glu²⁵, Lys^(26,30), 0.3 Aib²⁹]hPTHrP(1-34)NH₂[Glu^(22,25), Leu^(23,31), Lys^(26,30), Ahe²⁸, 0.5 Aib²⁹]hPTHrP(1-34)NH₂[Cha²², Ahc²³, Glu²⁵, Lys^(26,30), Leu^(28,31), 0.4Aib²⁹]hPTHrP(1-34)NH₂

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

1-67. (canceled)
 68. A method of treating osteoporosis in a patient inneed thereof, which comprises administering to said patient a peptide ofthe formula:

wherein A₁ is Ser, Ala or Dap; A₃ is Ser, Thr or Aib; A₅ is Leu, Nle,Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, ahalogen or CH₃; A₇ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe orp-X-Phe in which X is OH, a halogen or CH₃; A₈ is Met, Nva, Leu, Val,Ile, Cha, Acc or Nle; A₁₁ is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc,Phe or p-X-Phe in which X is OH, a halogen, or CH₃; A₁₂ is Gly, Acc orAib; A₁₅ is Leu, Nle, IIe, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe inwhich X is OH, a halogen or CH₃; A₁₆ is Ser, Asn, Ala, or Aib; A₁₇ isSer, Thr, or Aib; A₁₈ is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha or Aib;A₁₉ is Glu or Aib; A₂₁ is Val, Acc, Cha or Met; A₂₃ is Trp, Acc or Cha;A₂₄ is Leu, Acc or Cha; A₂₇ is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;A₂₈ is Leu, Acc or Cha; A₂₉ is Gln, Acc or Aib; A₃₀ is Asp or Lys; A₃₁is Val, Leu, Nle, Acc, Cha, or deleted; A₃₂ is His or deleted; A₃₃ isAsn or deleted; A₃₄ is Phe, Tyr, Amp, Aib, or deleted; each of R₁ and R₂is, independently, H, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀ phenylalkyl,C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂ hydroxyalkenyl, C₇₋₂₀hydroxyphenylalkyl or C₁₁₋₂₀ hydroxynaphthylalkyl; or one and only oneof R₁ and R₂ is COE₁ in which E₁ is C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₇₋₂₀phenylalkyl, C₁₁₋₂₀ naphthylalkyl, C₁₋₁₂ hydroxyalkyl, C₂₋₁₂hydroxyalkenyl, C₇₋₂₀ hydroxy-phenylalkyl or C₁₁₋₂₀hydroxynaphthylalkyl; and R³ is OH, NH₂, C₁₋₁₂ alkoxy or NH—Y—CH₂—Z inwhich Y is a C₁₋₁₂ hydrocarbon moiety and Z is H, OH, CO₂H or CONH₂;provided that at least one of A₅, A₇, A₈, A₁₁, A₁₂, A₁₅, A₁₈, A₂₁, A₂₃,A₂₄, A₂₇, A₂₈, A₂₉ and A₃₁ is Acc; or a pharmaceutically acceptable saltthereof.
 69. The method according to claim 68, further comprisingadministering to said patient a bisphosphonate or calcitonin.